AMP-activated protein kinase (AMPK) is emerging as a key sensor of brain energy balance. In the periphery, AMPK acutely regulates cellular metabolism and chronically regulates gene expression, reducing energy storage and increasing energy production (glycolysis, fatty acid oxidation and glycogen utilization). We have demonstrated that AMPK is highly expressed in brain and is rapidly activated in energy deprived states such as ischemia. However, the consequences of AMPK activation in stroke may be complex as the two major types of brain cells, neurons and astrocytes, are metabolically distinct. Unlike peripheral tissues, neurons are lacking the key enzymes to produce ATP via glycolysis, the major ATP-generating pathway activated during ischemia. In addition, neurons do not oxidize fatty acids efficiently, and have no glycogen stores. Therefore it could be predicted that activating catabolic processes by up-regulation of neuronal AMPK during severe ischemia would propagate metabolic failure and acidosis. In contrast, astrocytes can perform glycolysis, oxidize fatty acids to form ketones, and store some glycogen providing an energy supply for ischemic neurons. Compelling evidence additionally demonstrates that through ATP production and release, astrocytes may protect neurons by reducing excitotoxicity, lowering calcium influx and decreasing microglia mediated inflammation. Activation of astrocytic AMPK will likely reduce cerebral ischemic injury. This highlights the importance of examining the effect of loss of AMPK selectively in astrocytes or neurons following stroke. We have developed mice that are deficient in the catalytic isoforms of AMPK in either neurons or astrocytes. We found that mice deficient in AMPK in astrocytes had worse functional recovery after stroke;interestingly we also observed increased hemorrhagic transformation in these astrocytic KO mice after stroke. The overall goal of this proposal is to first characterize stroke outcome on cel specific AMPK manipulation and secondly determine the metabolic response to such manipulation. Selectively targeting AMPK signaling, a fundamental metabolic pathway, will not only provide us with a better scientific understanding of basic neuronal and astrocytic energy dynamics, but will also allow us to identify cellular specific targets for future clinical development.

Public Health Relevance

Stroke is the third leading cause of death in the U.S., and the most common cause of disability. AMPK is a key energy metabolic sensor, but its role in neurons and astrocytes may differ and produce significant and distinct effects on stroke outcome. In this application, we will initiate a focused investigation on the consequences of cell selective AMPK deletion an attempt to develop novel and specific treatments for stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS079137-02
Application #
8539647
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2012-09-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$221,039
Indirect Cost
$76,289
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Venna, Venugopal R; Li, Jun; Hammond, Matthew D et al. (2014) Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci 39:2129-38
Liu, Lin; Doran, Sarah; Xu, Yan et al. (2014) Inhibition of mitogen-activated protein kinase phosphatase-1 (MKP-1) increases experimental stroke injury. Exp Neurol 261:404-11